Pharmacogenetic Studies[unreadable] Pharmacogenetics involves the study of host susceptibility and environmental exposures in cancer development. The unique contribution of this discipline is that common genes are studied, and the role of the environment is more explicit because the mechanism of the putative polymorphic gene of interest is known. The study base is the population, but family studies often complement this work. We primarily focus on molecular epidemiology studies involving lung and lymphoproliferative cancers and occasionally explore special exposures such as dioxin. The major aim is to identify and better understand genetic components that contribute to major cancers. The studies involve interdisciplinary efforts and emphasize the integration of epidemiological, genetic, and laboratory approaches. Lung Cancer: GEB has been a pioneer in studies aimed at identifying a genetic component to common cancers using epidemiological study designs and we currently have a large lung cancer case-control study in the field (see below). Early work emphasized polymorphic genes (e.g., CYP2D6, GSTM1) that are hypothesized to activate or detoxify carcinogens and thereby alter an individual's susceptibility to cancer when exposed to a specific agent. Lung cancer is a logical focus for these studies, because the environmental agent is well characterized (i.e., tobacco smoking), although only a minority of heavy smokers develop the disease. Furthermore, somatic gene mutations are well documented in lung tumors and relatives of people who develop the cancer are also at increased risk. To better understand the genetic component to smoking-related cancer we have conducted case-control studies of lung cancer with extensive biospecimen collection; studied determinants of the cancer in nonsmokers; studied cancer in different geographic, occupational, and ethnic groups; and examined tumor mutations in consecutive surgical cases. We are currently involved in studies to evaluate whether genes contribute to precursor conditions (i.e. emphysema) or to the key exposure (i.e. smoking). Families with lung and other smoking-related cancers have been studied, although suitable large, multi generation families are challenging to accrue because of the death toll for smoking-related diseases. Integrated Studies: In our single largest study, we are investigating the genetic determinants of lung cancer and smoking in a multi-hospital, population-based case-control study of lung cancer with sufficient power to detect gene-environment interactions, biospecimen collection to allow interdisciplinary study of biomarkers from normal and neoplastic tissue, tissue collection from lung cancer surgical cases, and the planned study of genetic determinants of smoking in controls. This study is currently in the field in Milan, Italy. We also participate in NCl's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study, which is a cohort study of 70,000 individuals in which large numbers of lung cancer cases will be identified over the next few years. Currently studies of the genetic determinants of emphysema and the genetic determinants of smoking are planned. A related component, the National Lung Cancer Screening Trial (NLST) is planning to randomize over 50,000 high risk subjects to chest x-ray or helical CT scan, a promising new imaging technique that may detect lung cancer in an early curable stage. We have proposed collection of biospecimens on the screened population so both early markers and molecular determinants of benign vs. malignant outcomes can be explored. We also plan to address the hypothesis of a genetic component to smoking itself. We have examined genetic polymorphisms affecting dopamine regulation and receptor stimulation as candidates for influencing genetic susceptibility to cigarette smoking.